title: Epstein-Barr virus-encoded BARF1 promotes proliferation of gastric carcinoma cells through regulation of NF-κB.
abstract: In Epstein-Barr virus (EBV)-infected gastric carcinoma, EBV-encoded BARF1 has been hypothesized to function as an oncogene. To evaluate cellular changes induced by BARF1, we isolated the full-length BARF1 gene from gastric carcinoma cells that were naturally infected with EBV and transfected BARF1 into EBV-negative gastric carcinoma cells. BARF1 protein was primarily secreted into culture supernatant and only marginally detectable within cells. Compared with gastric carcinoma cells containing empty vector, BARF1-expressing gastric carcinoma cells exhibited increased cell proliferation (P < 0.05). There were no significant differences in apoptosis, invasion, or migration between BARF1-expressing gastric carcinoma cells and empty vector-transfected cells. BARF1-expressing gastric carcinoma cells demonstrated increased nuclear expression of nuclear factor kappa B (NF-κB) RelA protein and increased NF-κB-dependent cyclin D1. The expression of p21(WAF1) was diminished by BARF1 transfection and increased by NF-κB inhibition. Proliferation of naturally EBV-infected gastric carcinoma cells was suppressed by BARF1 small interfering RNA (siRNA) (P < 0.05). Immunohistochemical analysis of 120 human gastric carcinoma tissues demonstrated increased expression of cyclin D1 and reduced expression of p21(WAF1) in EBV-positive samples versus EBV-negative gastric carcinomas (P < 0.05). In conclusion, the secreted BARF1 may stimulate proliferation of EBV-infected gastric carcinoma cells via upregulation of NF-κB/cyclin D1 and reduction of the cell cycle inhibitor p21(WAF1), thereby facilitating EBV-induced cancer progression.
authors.affiliation: Departments of Pathology, Seoul National University Boramae Hospital.
authors.forename: Mee Soo
authors.initials: MS
authors.lastname: Chang
authors.forename: Dong Ha
authors.initials: DH
authors.lastname: Kim
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Roh
authors.forename: Jaap M
authors.initials: JM
authors.lastname: Middeldorp
authors.forename: Yang Soo
authors.initials: YS
authors.lastname: Kim
authors.forename: Sunghan
authors.initials: S
authors.lastname: Kim
authors.forename: Seungbong
authors.initials: S
authors.lastname: Han
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Kim
authors.forename: Byung Lan
authors.initials: BL
authors.lastname: Lee
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Woo
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D005455:Fluorescent Antibody Technique; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006801:Humans; D007124:Immunoenzyme Techniques; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C086495:BARF1 protein, Human herpesvirus 4; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D012333:RNA, Messenger; D014764:Viral Proteins